Amino Acids, Peptides and Proteins in Organic Chemistry 
Volume 4 – Protection Reactions, Medicinal Chemistry, Combinatorial Synthesis

This is the fourth of five books in the Amino Acids, Peptides and Proteins in Organic Synthesis series.

Closing a gap in the literature, this is the only series to cover this important topic in organic and biochemistry. Drawing upon the combined expertise of the international ‘who’s who’ in amino acid research, these volumes represent a real benchmark for amino acid chemistry, providing a comprehensive discussion of the occurrence, uses and applications of amino acids and, by extension, their polymeric forms, peptides and proteins. The practical value of each volume is heightened by the inclusion of experimental procedures.

The fourth volume in this five-volume series is structured in three main sections. The first section is about protection reactions and amino acid-based peptidomimetics. The second, and most extensive, part is devoted to the medicinal chemistry of amino acids. It includes, among others, the chemistry of alpha- and beta amino acids, peptide drugs, and advances in N- and O-glycopeptide synthesis. The final part deals with amino acids in combinatorial synthesis. Methods, such as phage display, library peptide synthesis, and computational design are described.

Table of Content

PROTECTION REACTIONS
General Considerations
Alpha-Amino Protection (Nalpha-Protection)
Carboxy Protection
Side Chain Protection
Photocleavable Protections
Conclusions
Experimental Procedures

PART I: Amino Acid-Based Peptidomimetics

THE HUISGEN CYCLOADDITION IN PEPTIDOMIMETIC CHEMISTRY
Introduction
Huisgen [2+3] Cycloaddition Between Azides and Acetylenes
Mechanistic Consideration for the Cu-Huisgen and Ru-Huisgen Cycloaddition
Building Blocks for the Synthesis of Triazole Modified Peptidomimetics
Cyclic Triazole Peptidomimetics
Acylic Triazole Peptidomimetics
Useful Experimental Procedures

RECENT ADVANCES IN BETA-STRAND MIMETICS
Introduction
Macrocyclic Peptidomimetics
Acyclic Compounds
Aliphatic and Aromatic Carbocycles
Ligands Containing One Ring with One Heteroatom (N)
Ligands Containing One Ring or Multiple Rings with One Heteroatom (O, S)
Ligands Containing One Ring with Two Heteroatoms (N, N)
Ligands Containing One Ring with Two Heteroatoms (N, S) or Three Heteroatoms (N, N, S or N, N, N)
Ligands Containing Two Rings with One Heteroatom (N or O)
Ligands Containing Two Rings with Two or Three Heteroatoms (N, N or N, S or N, N, N)
Conclusions

PART II: Medicinal Chemistry of Amino Acids

MEDICINAL CHEMISTRY OF ALPHA-AMINO ACIDS
Introduction
Glutamic Acid
Conformational Restriction
Bioisosterism
Structure-Activity-Studies
Conclusions

MEDICINAL CHEMISTRY OF ALICYCLIC BETA-AMINO ACIDS
Introduction
Five-Membered Alicyclic Beta-Amino Acids
Six-Membered Alicyclic Beta-Amino Acids

MEDICINAL CHEMISTRY OF ALPHA-HYDROXY-BETA-AMINO ACIDS
Introduction
Alpha-Hydroxy-Beta-Amino Acids
Antibacterial Agents
Inhibitors of Aminopeptidases
Aspartyl Proteases Inhibitors
Paclitaxel and its Derivatives

PEPTIDE DRUGS
Lights and Shades of Peptide and Protein Drugs
Peptide Drugs Available on the Market
Approved Peptides in Oncology
Antimicrobial Peptides
Perspectives

ORAL BIOAVAILABILITY OF PEPTIDE AND PEPTIDOMIMETIC DRUGS
Introduction
Fundamental Considerations of Intestinal Absorption
Barriers Limiting Oral Peptide/Peptidomimetic Drug Bioavailability
Strategies to Improve Oral Bioavailability of Peptide-Based Drugs
Conclusions

ASYMMETRIC SYNTHESIS OF BETA-LACTAMS VIA THE STAUDINGER REACTION
Introduction
Staudinger Reaction
Influence of the Geometry of the Imine on Stereoselectivity in the Reaction
Influence of the Polarity of the Solvent on Stereoselectivity of the Reaction
Influence of the Isomerization of the Imine Prior to its Nucleophilic Attack onto the Ketene Stereoselectivity in the Reaction
Influence of the Order of Addition of the Reactants to the Reaction
Influence of Chiral Substituents on the Stereoselectivity of the Reaction
Asymmetric Induction from the Imine Component
Asymmetric Induction from the Ketene Component
Double Asymmetric Cycloinduction
Influence of Catalysts on the Stereoselectivity of the Reaction
Concludings

ADVANCES IN N- AND O-GLYCOPEPTIDE SYNTHESIS – A TOOL TO STUDY CLYCOSYLATION AND DEVELOP NEW THERAPEUTICS
Introduction
Synthesis of O-Glycopeptides
Synthesis of N-Glycopeptides

RECENT DEVELOPMENTS IN NEOGLYCOPEPTIDE SYNTHESIS
Introduction
Neoglycoside and Neoglycopeptide Synthesis
Protein Side-Chain Modifications
Cu(I)-Catalyzed Azide-Alkyne ‘Click’ Cycloaddition
Cross-Metathesis
Application of Neoglycopeptides as Synthetic Vaccines
Enzymatic, Molecular and Cell Biological Techniques

PART III: Amino Acids in Combinatorial Synthesis

COMBINATORIAL/LIBRARY PEPTIDE SYNTHESIS
Introduction
High-Throughput Synthesis of Peptides
Synthesis of Peptide Arrays
Peptide Libraries
Future of Peptide Libraries
Synthetic Protocols

PHAGE-DISPLAYED COMBINATORIAL PEPTIDES
Introduction
Conclusions

DESIGNING NEW PROTEINS
Introduction
Protein Design Methods
Protocol for Protein Design
Conclusions

AMINO ACID-BASED DENDRIMERS
Introduction
Peptide Dendrimer Synthesis: Divergent and Convergent Approaches
Applications of Peptide Dendrimers
Conclusions

About the author

Andrew Hughes is a reader and Head of the Department of Chemistry, La Trobe University, Melbourne, Australia. He obtained his degrees from the University of Western Australia before taking up post-doctoral appointments at the University of Cambridge starting 1989. After three years working with Professor Andrew Holmes, he joined Professor Steven Ley´s group. While at Cambridge he was appointed the Shell Research Fellow at Robinson College. His interests lie in the general field of asymmetric synthesis and methodology, with a recent focus on amino acid chemistry.